This project tests the hypothesis that the process that leads to disease susceptibility, disability and frailty in older persons is mostly connected with a progressive dysregulation and reduced researve in the network of biological mechanisms that interact to amintain a stable energetic homeostasis, or to regain some equilibrium when the homestasis is critically challenged by a stressful event. The elements of these network are not completely defined but certainly include: 1. Intake of the essential elements that the body requires to create energy, including both the nutrients and oxygen;2. Activities that affect the different forms of energy utilization, including resting metabolic rate, physical activity, cognitive activity and nutrition;3) Neurological control of the energy flow, mostly affected by the interplay between the sympathetic and the parasympathetic nervous system. THis is the regulatory system that is in change of rapid adjustments, such as those that occur with rapid changes in temperature, or after bleeding;4) The endocrine system , which is also in charge of modulating the locoregional distribution of energy flow, but acts more slowly than the ANS;5. The production of Oxygen Free Radicals (ROS) during the aerobic metabolism has important signaling properties but can also produce large damage to all sort of macromolecules. Therefore, organism have elaborated different mechanism to scavenge ROS and reduce their toxicity. When the flow of energy is reduced or accelerated, the production of ROS tend to increase and if not completely buffered by antioxidant system, can cause severe damage;6. Ultimately, any type of damage triggers an inflammatory response, which is turn causes the organism to segregate the energy utilization to the function that are supposed to fight the "aggression" to the host. Biomarkers for these 6 systems have been developed over the last few years and some of them use high throughput assays that allow their utilization in epidemiological studies. However, no current study has the broad range of information required to address the multysistem dysregulation hypothesis in an epidemiological setting. Therefore, we have identified a number of studies that have some of these information available and that can be used to test one or more partial components of our general hypothesis. By creating a network of collaboration with the research groups that are conducting those studies, we have gained access to data that complement those that we are already collecting in the BLSA. In particular, in the context of this project, we intend to use data from: a. The Baltimore Longitudinal STudy of Aging b. The InChianti Study c. The SardiNIA study d. The Women's Health and Aging Study e. The Health ABC Study f. The ICare/Dicomano Study g. The ASSI italian Initiative h. The ILSA Study i. The Il Sirente Study l. The AGES study. Collaborations between the LSS and the investigators of these studies have been already established. Other studies could be included in this initiative, based on opportiniries and needs of the research group. In the intial period of this project, we will test univariate hypothesis of an indepdent correlation between the different homeostatic domain and their association with geriatric-relevant outcomes, such as morbidity, frailty, disabilitya nd mortality. In thes econd phase of this project, we will attempt to study the effect on outcome of multiple biomarkers and physiological measures, within a specific domain and across different domains. The second part of this project requires some metodological and statistical development. This methodological component is considered an essential component of the project and will be conducted in collaboration with multiple academic institutions.